Cyclohexyl(alkyl)-propanolamines, preparation method and pharmaceutical compositions containing same

ABSTRACT

The present invention relates to the compounds of formula (I): 
                         
in which A is a group of formula (a) or (b)
 
                         
in which R represents a hydrogen or halogen atom, an —S(O) z (C 1 –C 4 )alkyl group, an —NHSO 2 (C 1 –C 4 )alkyl group, an —SO 2 NH(C 1 –C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 –C 4 )alkyl group or an —NHSO 2 phenyl group, said phenyl possibly being substituted with a halogen atom, with a (C 1 –C 4 )alkyl group or with a (C 1 –C 4 )alkoxy group; R 1  represents a hydrogen atom or a (C 1 –C 4 )alkyl group, a —CO(C 1 –C 4 )alkyl group, a phenyl-(C 1 –C 4 )alkyl group or a —COphenyl group, said phenyl also possibly being substituted with a halogen atom or with a (C 1 –C 4 )alkoxy group; R 2  is a hydrogen atom or an —SO 2 (C 1 –C 4 )alkyl group, an —SO 2 phenyl-(C 1 –C 4 )alkyl group or an —SO 2 phenyl group; X completes a ring of 5 to 8 atoms, said ring being saturated or unsaturated, possibly being substituted with one or two (C 1 –C 4 )alkyl groups and bearing one or two carbonyl groups; n, m and z are, independently, 0, 1 or 2; R 3  represents a hydrogen or halogen atom, a (C 1 –C 6 )alkyl group, a (C 1 –C 4 )alkoxy group, a —COO(C 1 –C 4 )alkyl group, a —CO(C 1 –C 4 )alkyl group, an —NHSO 2 (C 1 –C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 –C 4 )alkyl groups, —NO 2 , —CN, —CONR 4 R 5 , —COOH, or a 4,5-dihydro-1,3-oxazol-2-yl or 4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl group; R 4  and R 5  represent, independently, a hydrogen atom, a phenyl, a (C 1 –C 4 )alkyl group or a phenyl-(C 1 –C 4 )alkyl group or R 4  and R 5  with the nitrogen atom to which they are attached, may form a ring of 5 to 7 atoms in total; and to the salts or solvates thereof, to the pharmaceutical compositions containing them, to a process for the preparation thereof and to intermediates in this process.

The instant application is a National Stage 371 Application ofPCT/FR01/03784, filed Nov. 30, 2001 and claims priority to foreignapplication France 0015477, filed on Nov. 30, 2000.

The present invention relates to novel cyclohexyl(alkyl)propanolamines,to the pharmaceutical compositions containing them, to a process for thepreparation thereof and to synthesis intermediates in this process.

WO 99/65895 describes phenoxypropanolamines in which the amine bears asubstituted piperidine, these compounds showing agonist activity withrespect to the beta-3 adrenergic receptor.

The beta-3 adrenergic receptor has been the subject of many studiesaimed at synthesizing compounds which are agonists with respect to thisreceptor, these compounds exerting a considerable anti-obesity andanti-diabetic effect in humans, as described, for example, by Weyer, Cet al., Diabetes Metab., 1999, 25(1):11–21.

It has now been found that certain propanolamines bearing acyclohexyl(alkyl) group on the amine possess a powerful agonist activitywith respect to beta-3 adrenergic receptors.

Thus, the present invention relates, according to one of its aspects, tocyclohexyl(alkyl)propanolamines of formula (I):

in which

A is a group of formula (a) or (b)

where

-   -   R represents a hydrogen or halogen atom, an        —S(O)_(z)(C₁–C₄)alkyl group, an —NHSO₂(C₁–C₄)alkyl group, an        —SO₂NH(C₁–C₄)alkyl group, an —NHSO₂phenyl-(C₁–C₄)alkyl group or        an —NHSO₂phenyl group, said phenyl possibly being substituted        with a halogen atom, with a (C₁–C₄)alkyl group or with a        (C₁–C₄)alkoxy group;    -   R₁ represents a hydrogen atom or a (C₁–C₄)alkyl group, a        —CO(C₁–C₄)alkyl group, a phenyl-(C₁–C₄)alkyl group or a        —CO-phenyl group, said phenyl possibly being substituted with a        halogen atom or with a (C₁–C₄)alkoxy group;    -   R₂ is a hydrogen atom, an —SO₂(C₁–C₄)alkyl group, an        —SO₂phenyl-(C₁–C₄)alkyl group or an —SO₂phenyl group;    -   X completes a ring of 5 to 8 atoms, said ring being saturated or        unsaturated, possibly being substituted with one or two        (C₁–C₄)alkyl groups and bearing one or two carbonyl groups;    -   n, m and z are, independently, 0, 1 or 2;    -   R₃ represents a hydrogen or halogen atom, a (C₁–C₆)alkyl group,        a (C₁–C₄)alkoxy group, a —COO(C₁–C₄)alkyl group, a        —CO(C₁–C₄)alkyl group, an —NHSO₂(C₁–C₄)alkyl group, an        —NHSO₂phenyl-(C₁–C₄)alkyl group, —NO₂, —CN, —CONR₄R₅, —COOH, or        a 4,5-dihydro-1,3-oxazol-2-yl or        4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl group;    -   R₄ and R₅ represent, independently, a hydrogen atom, a phenyl, a        (C₁–C₄)alkyl group or a phenyl-(C₁–C₄)alkyl group;    -   or    -   R₄ and R₅ with the nitrogen atom to which they are attached, may        form a ring of 5 to 7 atoms in total;    -   and the salts or solvates thereof.

In the present description, the terms “(C₁–C₄)alkyl” and “(C₁–C₆)alkyl”denote monovalent radicals formed from a respectively C₁–C₄ and C₁–C₆hydrocarbon containing a straight or branched saturated chain.

In the present description, the term “halogen” denotes an atom chosenfrom chlorine, bromine, iodine and fluorine.

Preferred compounds are those in which n and m are each zero.

Other preferred compounds are those in which R₁ is a hydrogen atom.

Other preferred compounds are those in which R is chosen from an—NHSO₂(C₁–C₄)alkyl group, an —NHSO₂phenyl-(C₁–C₄)alkyl group or an—NHSO₂phenyl group.

Other preferred compounds are those in which R₃ is —COO(C₁–C₄)alkyl or—CO(C₁–C₄)alkyl or CONR₄R₅.

Other preferred compounds are those in which R₃ is in position 4 of thebenzene.

Other preferred compounds are those in which z is 2.

Other preferred compounds are those in which X is a methylene, anethylene or a propylene.

Other preferred compounds are those in which X is a carbonyl, a—CO—CO—group, a —CO—C((C₁–C₄)alkyl)₂-CO— group, a methylenemonosubstituted or disubstituted with (C₁–C₄)alkyl or a —COCH₂— group.

Preferred —NHSO₂phenyl-(C₁–C₄)alkyl and —SO₂phenyl-(C₁–C₄)alkyl groupsare, respectively, benzylsulphonylamino and benzylsulphonyl.

When R₄ and R₅ form, with the nitrogen atom to which they are attached,a ring of 5 to 7 atoms, preferred rings are piperidine and pyrrolidine.

The salts of the compounds of formula (I) according to the presentinvention comprise both the addition salts with pharmaceuticallyacceptable inorganic or organic acids, such as hydrochlorate,hydrobromate, sulphate, hydrogen sulphate, dihydrogen phosphate,citrate, maleate, tartrate, fumarate, gluconate, methanesulphonate,2-naphtalenesulphonate, etc., and the addition salts which allowsuitable separation or crystallization of the compounds of formula (I),such as picrate or oxalate, or the addition salts with optically activeacids, for example camphosulphonic acids and mandelic or substitutedmandelic acids.

When the compounds of formula (I) have a free carboxyl group, the saltsalso comprise the salts with inorganic bases, preferably those withalkaline metals such as sodium or potassium, or with organic bases.

The optically pure stereoisomers, and also the mixtures of isomers ofthe compounds of formula (I), due to the asymmetric carbon, in anyproportion, are also part of the present invention.

Preferred compounds of formula (I) are the compounds in which theconfiguration of the carbon of the propanolamine bearing the OH group is(S).

The compounds of formula (I) may be in the form of “cis” or “trans”geometrical isomers, depending on the relative position of thesubstituents in positions 1 and 4 of the cyclohexyl ring (marked with astar). These pure isomers and their mixtures, in any proportion, arepart of the present invention.

The mixtures of optical and geometrical stereoisomers above, in anyproportion, are also part of the present invention.

The compounds of formula (I) may be prepared by treating a compound offormula (II):

in which A is as indicated above, with an amine of formula (III)

in which n, m and R₃ are as defined above and, optionally, transformingthe compound of formula (I) thus obtained into a salt or solvatethereof.

More particularly, the reaction between the compounds of formulae (II)and (III) is carried out in an organic solvent, such as a lower alcohol,for instance methanol, ethanol, isopropanol and tert-butanol; dimethylsulphoxide; a linear or cyclic ether; an amide such as dimethylformamideor dimethylacetamide or mixtures of these solvents; preferably using atleast equimolecular amounts of the reagents.

The temperature of the reaction is between room temperature and thereflux temperature of the solvent chosen.

When R₁ represents hydrogen, it is preferable to protect the functionalgroup with a protective group in order to increase the yield of thereaction. As protective groups, use may be made of the protective groupswhich are conventional for phenol groups, such as for examplemethoxyethoxymethyl (MEM), trimethylsilylethoxymethyl (SEM), benzyl,optionally substituted, or benzoyl, according to well-known techniques.

Other functional groups optionally present (amino groups for example)may, themselves, also be protected by suitable protective groupsaccording to well-known conventional techniques.

The compounds of formula (II) are compounds which are known in theliterature or they may be prepared using processes similar to describedprocesses.

The compounds of formula (III) may be prepared using an intermediate offormula (IX) obtained according to the following Scheme 1.

In the formulae of Scheme 1, m is as defined above and Hal represents ahalogen, preferably bromine, while R′₃ is a 4,5-dihydro-1,3-oxazol-2-yl,4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl, (C₁–C₄)alkyl or (C₁–C₄)alkoxygroup.

These are reactions which are well-known to those skilled in the art;the condensation step may, for example, be carried out in a way similarto that described by Meyers et al., J. Org. Chem., 1974, 39: 2787. Theintermediate alcohol (VI) is transformed into the derivative (VII), forexample according to the method described in A. M. Gonzales-Cameno etal., Tetrahedron, 1994, 50: 10971 or with POCl₃ as described in Org.Prep. Proced. Int., 1995, 27: 122, and then into the saturatedderivative (VIII) via a conventional reduction reaction. The hydrolysisof the acetal group may be carried out in a way similar to the reactiondescribed by C. Szantay et al., Tetrahedron, 1996, 52(33): 11053.

The intermediate of formula (IX) may be used to prepare the compounds offormula (III) by transforming, for example, the carbonyl group of thecyclohexane into an amino group by reduction of the corresponding oximeor, when n is 1 or 2, into an aminoalkyl group by reaction with acyanide or nitromethane, or by the Wittig reaction with the desiredphosphonate, according to well-known reactions.

When R′₃ is a 4,5-dihydro-1,3-oxazol-2-yl or4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl group, the compound of formula(III) in which R₃ is —COOH is easily obtained by hydrolysis.

Most of the compounds of formula (III), such as for example those inwhich R₃ is —CN, —CO(C₁–C₄)alkyl, —COO(C₁–C₄)alkyl, a sulphonamidogroup, a halogen atom or —NO₂, may then be obtained by transformation ofthe compound of formula (III) in which R₃ is —COOH, according toreactions well-known to those skilled in the art, after protection ofthe NH₂ group with a protective group such as, for example, the BOCgroup and/or benzyl.

Alternatively, use may be made, as a starting product, of the compoundof formula (V) in which R′₃ is —CN, and m=1; in this case, thecondensation of step (a) is carried out as described, for example, in J.Med. Chem., 1992, 35: 320 and the product (III) obtained at the end ofthe process above is easily transformed into the derivatives in which R₃is —COOH, —CO(C₁–C₄)alkyl or —CONR₄R₅, after protection of the NH₂ groupwith a protective group such as, for example, the BOC(tert-butoxycarbonyl) group and/or benzyl.

The “cis” and “trans” isomers may be obtained by separation of themixture, for example by chromatography or by selective crystallization,according to conventional processes.

The activity of the compounds of the present invention with respect tobeta-3 activity was demonstrated using in vitro tests on human colonaccording to the method described by T. Croci et al., Br. J. Pharmacol.,1997, 122: 139P, by L. Manara et al., Gut, 2000, 47: 337–342 and inEP-B-436435.

More particularly, it was noted that the compounds of formula (I) aremuch more active on the isolated colon than on the atrium and on thetrachea.

These surprising properties of the compounds of formula (I) make itpossible to envisage their use as medicinal products with beta-3 agonistaction.

In addition, the compounds of formula (I) are relatively nontoxic; inparticular, their acute toxicity is compatible with their use asmedicinal products for treating diseases in which compounds having anaffinity for the beta-3 receptor, in particular beta-3 agonists, are ofuse. Such diseases are described in the literature. The compounds offormula (I), and also the pharmaceutically acceptable salts thereof, maytherefore, for example, be indicated in the treatment ofgastrointestinal diseases such as inflammatory diseases of theintestine, for instance irritable bowel disease (IBD), as modulators ofintestinal motivity, as lipolytic agents, anti-obesity agents,anti-diabetic agents, psychotropic agents, anti-glaucoma agents,cicatrizing agents and anti-depressants, as inhibitors of uterinecontractions, as tocolytics for preventing or delaying preterm births,and for the treatment and/or prophylaxis of dysmenorrhoea. In addition,the compounds of formula (I) may be used in the treatment of certaindiseases of the central nervous system, such as for example depression,and also of certain disorders of the urinary system, such as urinaryincontinence.

The use of compounds of formula (I) above, and also that of thepharmaceutically acceptable salts and solvates thereof, for preparingthe medicinal products above, constitutes a subsequent aspect of thepresent invention.

For such a use, an effective amount of a compound of formula (I), or ofa pharmaceutically acceptable salt or solvate thereof, is administeredto the mammals which require such a treatment.

The compounds of formula (I) above, and the pharmaceutically acceptablesalts and solvates thereof, may be used at daily doses of 0.01 to 20 mgper kilo of body weight of the mammal to be treated, preferably at dailydoses of from 0.1 to 10 mg/kg. In humans, the dose may vary preferablyfrom 0.5 mg to 1500 mg per day, in particular from 2.5 to 500 mg,depending on the age of the individual to be treated, the type oftreatment, prophylactic or curative, and the seriousness of thedisorder. The compounds of formula (I) are generally administered as adosage unit of 0.1 to 500 mg, preferably of 0.5 to 100 mg, of activeprinciple, one to five times a day.

Said dosage units are preferably formulated in pharmaceuticalcompositions in which the active principle is mixed with apharmaceutical excipient.

Thus, according to another of its aspects, the present invention relatesto pharmaceutical compositions containing, as an active principle, acompound of formula (I) above or a pharmaceutically acceptable salt orsolvate thereof.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,transdermal or rectal administration, the active ingredients of formula(I) above, and the pharmaceutically acceptable salts and solvatesthereof, may be administered in unit administration forms, mixed withconventional pharmaceutical supports, to animals and humans for treatingthe abovementioned disorders. The unit administration forms which aresuitable comprise oral forms such as tablets, gel capsules, powders,granules and oral solutions or suspensions, sublingual and buccaladministration forms, subcutaneous, intramuscular or intravenousadministration forms, local administration forms and rectaladministration forms.

When a solid composition in the form of tablets is prepared, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets may be coated with sucrose or other suitablematerials, or they may be treated such that they have sustained ordelayed activity and that they release, in a continuous manner, apredetermined amount of active principle.

A preparation of gel capsules is obtained by mixing the activeingredient with a diluent and pouring the mixture obtained into soft orhard gel capsules.

A preparation in the form of a syrup or elixir may contain the activeingredient together with a sweetener, preferably a calorie-freesweetener, methylparaben and propylparaben as antiseptics, and also aflavour enhancer and a suitable colorant.

The water-dispersible powders or granules may contain the activeingredient mixed with dispersing agents or wetting agents, or suspendingagents, such as polyvinylpyrrolidone, and also with sweeteners orflavour correctors.

For local administration, the active principle is mixed into anexcipient for preparing creams or ointments, or it is dissolved in avehicle for intraocular administration, for example in the form of aneyewash.

For rectal administration, use is made of suppositories prepared withbinders which melt at rectal temperature, for example cocoa butter orpolyethylene glycols.

For parenteral administration, aqueous suspensions, saline solutions orinjectable sterile solutions which contain pharmacologically compatibledispersion agents and/or wetting agents, for example propylene glycol orbutylene glycol, are used.

The active principle may also be formulated in the form ofmicrocapsules, optionally with one or more supports or additives.

According to another of its aspects, the present invention relates to amethod for treating pathological conditions which are improved by abeta-3 agonist action, which comprises administering a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.

The compounds of formula (I), in particular the compounds (I) labelledwith an isotope, may also be used as laboratory tools in biochemicalassays.

The compounds of formula (I) bind to the beta-3 adrenergic receptor.These compounds may therefore be used in a conventional binding assay,in which an organic tissue in which this receptor is particularlyabundant is used, and the amount of compound (I) displaced by a testcompound is measured, in order to evaluate the affinity of said compoundwith respect to the binding sites of this particular receptor

Another specific subject of the present invention is therefore a reagentwhich can be used in biochemical assays, which comprises at least onesuitably labelled compound of formula (I).

The following examples illustrate the invention more clearly. In theseexamples, the following abbreviations may be used:

Ph=phenyl; Bn=benzyl; Me=methyl; Et=ethyl; Bu=butyl;Ox=4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl.

PREPARATION 1 Ethyl 4-(4-oxocyclohexyl)benzoate (i)8-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]-1,4-dioxaspiro[4,5]decan-8-ol

A solution of 8 g of2-(4-bromophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (31.5 mmol) in 15ml of anhydrous THF is poured dropwise onto 956 mg of Mg (39.3 mmol) insuch a way as to maintain the mixture at the reflux temperature and themixture is refluxed for 2.5 hours. The mixture is cooled to roomtemperature and a solution of 5.41 g of 1,4-cyclohexandionemonoethyleneacetal (34.65 mmol) in 20 ml of anhydrous THF is added to itdropwise. The mixture is stirred at room temperature for 1.5 hours andthen at reflux temperature for 1 hour. The mixture is poured into 500 mlof a 10% NH₄Cl solution and extracted with ethyl acetate. The organicphase is dried and, after filtration, the solvent is evaporated offunder reduced pressure. The residue is crystallized in ethyl acetate.The product of the title is obtained in the form of a white solid.

M.p. 146–148° C.

(ii)2-[4-(1,4-Dioxaspiro[4,5]dec-7-en-8-yl)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole

73.5 ml of pyridine are added to a solution of 34 g of the product ofthe previous step (102.6 mmol) in 250 ml of methylene chloride; themixture is cooled to 0° C. and 15 ml of thionyl chloride (205 mmol) areadded to it dropwise over 15 minutes. After one hour, the cooling bathis removed and, one hour later, the mixture is refluxed for one hour.The solvent is evaporated off and 400 ml of water and 250 ml of ethylacetate are added. The organic phase is washed with a saturated aqueousNaCl solution. The aqueous phase is extracted with ethyl acetate, thepooled organic phases are dried and, after filtration, the solvent isevaporated off under reduced pressure. The product of the title isobtained in the form of a white solid which is crystallized in an ethylacetate/hexane mixture.

M.p. 109–111° C.

(iii)2-[4-(1,4-Dioxaspiro[4,5]dec-8-yl)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole

A solution of 33.1 g of the product of the previous step (105.6 mmol) in350 ml of absolute ethanol is hydrogenated in the presence of 4.0 g ofPd/C at 10%, at a pressure of 1 atmosphere and at 30° C., for 5 hours.The catalyst is filtered and the solvent is evaporated off. The residueis taken up in hexane and a white solid is filtered off. The compound ofthe title is thus obtained.

M.p. 128–140° C.

(iv) Ethyl 4-(4-oxocyclohexyl)benzoate

3 g of the product of step (iii) (9.51 mmol) are dissolved in 60 ml ofethanol and 4.0 ml of 96% sulphuric acid are added, and the mixture isrefluxed for 22 hours. The solvent is partially evaporated off and theremaining mixture is taken up with a mixture of 300 ml of a saturatedsodium bicarbonate solution and 150 ml of ethyl acetate. The organicphase is washed with a saturated aqueous NaCl solution. The organicphase is dried and, after filtration, the solvent is evaporated offunder reduced pressure. The crude product is purified by chromatographyon a silica gel column, eluting with an 8/2 hexane-ethyl acetatemixture. The compound of the title is obtained in the form of a solid.

M.p. 60–62° C.

PREPARATION 24-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]cyclohexanone

2 g of the product of step (iii) of Preparation 1 (6.34 mmol) aredissolved in 70 ml of acetone and 4 ml of 6N hydrochloric acid are addedto this. The mixture is stirred at room temperature for 20 hours. Thesolvent is evaporated off and the residue is taken up with a mixture of250 ml of a 5% sodium bicarbonate solution and 200 ml of ethyl acetate.The organic phase is washed with water and with a saturated aqueous NaClsolution. The organic phase is dried and, after filtration, the solventis evaporated off under reduced pressure. The crude product is purifiedby chromatography on a silica gel column, eluting with a 6/4hexane/ethyl acetate mixture. The compound of the title is obtained inthe form of a white solid.

M.p. 118–120° C.

PREPARATION 3 Ethyl 4-(4-aminocyclohexyl)benzoate (cis and trans) andhydrochlorate of the trans isomer (i) Ethyl4-[4-(methoxyimino)cyclohexyl]benzoate

2.88 g of the product of preparation 1 (11.7 mmol) are dissolved in 25ml of ethanol and 1.17 g of O-methyl-hydroxylamine (14 mmol) and 5 ml ofpyridine are added to this. The mixture is stirred at 50° C. for 4hours. The solvent is evaporated off and the residue is taken up with amixture of 50 ml of water and 50 ml of ethyl acetate. The organic phaseis washed with water and with a saturated aqueous NaCl solution. Theorganic phase is dried and, after filtration, the solvent is evaporatedoff under reduced pressure. The crude product is purified bychromatography on a silica gel column, eluting with a 90/10 hexane/ethylacetate mixture. The compound of the title is obtained in the form of awhite solid.

M.p. 74–76° C.

(ii) Ethyl 4-(4-aminocyclohexyl)benzoate (cis and trans) andhydrochlorate of the trans isomer

1.42 g of the product of the previous step (5.16 mmol) are dissolved in5 ml of THF, in a nitrogen atmosphere at 0° C., and 11.3 ml of a 1Msolution of boron hydride in THF (11.3 mmol) are added over 10 minutes.The mixture is stirred for 5 h at room temperature and then at refluxtemperature for 1 hour. 30 ml of ethanol are added to the mixture, whichis stirred for 1 hour at reflux temperature, and then 3 ml of ethanolsaturated with hydrochloric acid are added to this, followed by stirringat 70° C. for 2 hours. The solvent is evaporated off and the residue istaken up with a mixture of 40 ml of a saturated sodium bicarbonatesolution and 40 ml of ethyl acetate. The organic phase is washed with asaturated aqueous NaCl solution. The organic phase is dried and, afterfiltration, the solvent is evaporated off under reduced pressure. Thecrude product is purified by chromatography on a silica gel column,eluting with a 94/6/0.6 methylene chloride/methanol/NH₄OH mixture. The“trans” compound of the title is obtained in the form of a white solid.

M.p. 98–103° C.

The hydrochlorate of this compound is obtained by treating it with asolution of hydrochloric acid in ethanol.

M.p. 305–308° C.

The “cis” compound of the title is obtained in the form of a solid.

M.p. 46–48° C.

PREPARATION 44-Benzyloxy-1-((2S)2,3-epoxypropoxy)-3-(N-phenylsulphonyl-N-tert-butoxycarbonylamino)benzene(i) 4-Benzyloxy-3-(phenylsulphonylamino)phenyl acetate

A mixture of 5.0 g (0.0194 mol) of 4-benzyloxy-3-aminophenyl acetate,3.3 ml (0.0236 mol) of triethylamine and 3.0 ml (0.0236 mol) ofbenzenesulphonyl chloride in 150 ml of methylene chloride is stirred atroom temperature overnight. The mixture is then washed with water andthe organic phase is dried, followed by purification by chromatographyon a silica gel column, eluting with a 7/3 cyclohexane/ethyl acetatemixture. The compound of the title is obtained.

M.p. 109–111° C.

(ii) 4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-phenylsulphonylamino)phenylacetate

A mixture of 5.4 g (0.0136 mol) of the product of the previous step, 3.6g (0.0163 mol) of di-tert-butyl dicarbonate and 0.33 g (0.00272 mol) of4-dimethylaminopyridine in 100 ml of methylene chloride is stirred atroom temperature overnight. The solvent is then evaporated off and theproduct of the title thus obtained is recrystallized in ethyl acetate.

M.p. 172–174° C.

(iii) 4-Benzyloxy-3-(N-tert-butoxycarbonyl-N-phenylsulphonylamino)phenol

A mixture of 3.8 g (0.0076 mol) of the product of the previous step in200 ml of methanol and 9.1 ml of a 1M NaOH solution is stirred at roomtemperature for 40 minutes. Citric acid is then added until a pH of 6 isobtained and the solvent is evaporated off. The residue is taken up inmethylene chloride and washed with water, the organic phase is dried,the solvent is evaporated off and the product is treated in isopropylether. The compound of the title is obtained.

M.p. 170–172° C.

(iv)4-Benzyloxy-1-((2S)2,3-epoxypropoxy)-3-(N-phenylsulphonyl-N-tert-butoxycarbonylamino)benzene

A mixture of 2.9 g (0.0063 mol) of the product of the previous step, 2.9g of crushed potassium carbonate and 2.0 g (0.0078 mol) of(2S)(+)glycidyl nosylate in 150 ml of acetone is stirred at refluxtemperature overnight. The mixture is filtered, the solvent isevaporated off and the residue is purified by chromatography on a silicagel column, eluting with an 8/2 cyclohexane/ethyl acetate mixture. Thecompound of the title is obtained, which is recrystallized in ethylacetate.

M.p. 152–154° C.

PREPARATION 54-Benzyloxy-3-(N-n-butylsulphonyl-N-tert-butoxycarbonylamino)-1-((2S)2,3-epoxypropoxy)benzene

The compound of the title is obtained by carrying out the procedure asdescribed in Preparation 4, but using n-butylsulphonyl chloride insteadof benzenesulphonyl chloride.

M.p. 88–90° C.

PREPARATION 64-Benzyloxy-3-(N-benzylsulphonyl-N-tert-butoxycarbonylamino)-1-((2S)2,3-epoxypropoxy)benzene

The compound of the title is obtained by carrying out the procedure asdescribed in Preparation 4, but using benzylsulphonyl chloride insteadof benzenesulphonyl chloride.

M.p. 123–125° C.

PREPARATION 74-Benzyloxy-1-((2S)2,3-epoxypropoxy)-3-(N-methylsulphonyl-N-benzylamino)benzene(i) 4-Benzyloxy-3-(N-methylsulphonyl-N-benzylamino)phenyl acetate

A mixture of 7.7 g (0.023 mol) of4-benzyloxy-3-(N-methylsulphonylamino)phenyl acetate, 4.75 g (0.035 mol)of crushed potassium carbonate and 3.3 ml (0.0276 mol) of benzyl bromidein 150 ml of anhydrous acetone is stirred at reflux temperature for 4hours. After filtration and evaporation, the compound of the title isobtained, which is recrystallized in ethyl acetate.

M.p. 143–145° C.

(ii) 4-Benzyloxy-3-(N-benzyl-N-methylsulphonylamino)phenol

The compound of the title is obtained by carrying out the proceduredescribed in Preparation 4 (iii), but using the product of the previousstep.

M.p. 156–158° C.

(iii)4-Benzyloxy-1-((2S)2,3-epoxypropoxy)-3-(N-benzyl-N-methylsulphonylamino)benzene

The compound of the title is obtained by carrying out the proceduredescribed in Preparation 4 (iv), but using the product of the previousstep.

M.p. 112–113° C.

PREPARATION 8 trans-4-(4-Aminocyclohexyl)-N,N-diethylbenzamide (i)trans-Ethyl 4-(4-(N-benzyloxycarbonylamino)cyclohexyl)benzoate

A mixture of 2.0 g (0.0008 mol) of trans-ethyl4-(4-aminocyclohexyl)benzoate, 1.25 ml of triethylamine and 1.26 ml(0.0084 mol) of benzyl chloroformiate at 95% in 40 ml ofdimethylformamide is stirred at room temperature for 3 hours. Themixture is poured into water, extracted with ethyl acetate and dried,and the solvent is evaporated off. The residue is purified bychromatography on a silica gel column, eluting with an 8/2cyclohexane/ethyl acetate mixture. The compound of the title isobtained.

M.p. 158–160° C.

(ii) trans-4-(4-(N-Benzyloxycarbonylamino)cyclohexyl)benzoic acid

The ester of the previous step is hydrolysed with a solution ofethanol/tetrahydrofuran in the presence of NaOH. The compound of thetitle is obtained.

M.p. 249–251° C.

(iii)trans-4-(4-(N-Benzyloxycarbonylamino)cyclohexyl)-N,N-diethylbenzamide

A mixture of 650 mg (1.84 mmol) of the product of the previous step, 814g (1.84 mmol) of BOP, 0.190 ml (1.84 mmol) of diethylamine and 0.258 ml(1.84 mmol) of triethylamine in 30 ml of methylene chloride is heated at40° C. for 5 hours and then at room temperature overnight. The solventis evaporated off and the residue is taken up in ethyl acetate andwashed with a sodium bicarbonate solution and then with an aqueousacetic acid solution; the organic phase is dried and the solvent isevaporated off. The residue is purified by chromatography on a silicagel column, eluting with a 1/1 cyclohexane/ethyl acetate mixture. Thecompound of the title is obtained.

M.p. 122–125° C.

(iv) trans-4-(4-Aminocyclohexyl)-N,N-diethylbenzamide

A solution of 610 mg of the product of the previous step in 20 ml ofethanol is stirred at a temperature of 40° C. in a hydrogen atmospherefor 7 hours in the presence of 70 mg of Pd/C at 10%. The catalyst isfiltered and the solvent is evaporated off under reduced pressure, andthe product is treated with ethyl ether. The compound of the title isobtained.

M.p. 180–182° C.

PREPARATION 9 trans-4-(4-Aminocyclohexyl)-N-butylbenzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Preparation 8 (iii) and (iv), but using n-butylamineinstead of diethylamine.

M.p. 108–110° C.

PREPARATION 10 trans-(4-N-Benzylaminocyclohexyl)benzene

5.0 g of 4-phenylcyclohexanone (0.028 mol), 3.32 g of benzylamine (0.031mol), 2.14 g of NaBH₃CN (0.034 mol) (added at 0° C.) and 3.75 g ofacetic acid in 100 ml of ethanol are mixed and stirred overnight at roomtemperature. A 1N sodium bicarbonate solution is then added, the mixtureis stirred at room temperature for 3 hours, the ethanol is evaporatedoff, the remainder is extracted with ethyl acetate and the solvent isevaporated off. The product is dissolved in ethanol, a 3N HCl/ethanolsolution is added to this and the mixture is stirred for 3 hours. It isbrought to basic pH with a 1N sodium bicarbonate solution, the ethanolis evaporated off and, after extraction with ethyl acetate, the organicphase is dried and the solvent is evaporated off. A mixture of cis andtrans isomer is obtained, which is separated by flash chromatography,eluting with a 98/2/0.2 methylene chloride/methanol/NH₄OH mixture. Thecompound of the title is obtained as a white solid (R.f. lower comparedto the cis isomer).

PREPARATION 11 trans-1-(4-N-Benzylaminocyclohexyl)benzonitrile

A mixture of cis and trans isomer is obtained by carrying out theprocedure as described in Preparation 10, but using4-(4-cyanophenyl)cyclohexanone instead of 4-phenylcyclohexanone, whichmixture is separated by flash chromatography, eluting with a 9/1chloroform/methanol mixture. The compound of the title is obtained as awhite solid (R.f. lower compared to the cis isomer—semi-solid).

M.p. 117–119° C.

PREPARATION 12 trans-4-(4-N-Benzylaminocyclohexyl)benzamide

1.1 g (3.90 mmol) of the product of Preparation 11, 1 ml of 20% NaOH and1 ml of 30% H₂O₂ are mixed. The mixture is stirred at room temperaturefor 15 minutes and then 5 ml of methanol are slowly added. A yellowsolution is obtained which is vigorously stirred for 5 hours. The whitesolution thus obtained is diluted with 50 ml of water and the mixture isextracted with methylene chloride. The organic phase is dried and thesolvent is evaporated off. The product is treated in diethyl ether. Theproduct of the title is obtained.

M.p. 207–210° C.

PREPARATION 134-Methoxy-3-[(N-methylsulphonyl-N-tert-butoxycarbonyl)amino]-1-((2S)2,3-epoxypropoxy)benzene

The compound of the title is obtained by carrying out the procedure asdescribed in Preparation 4 (ii), (iii) and (iv), but using4-methoxy-3-(methylsulphonylamino)phenyl acetate instead of4-benzyloxy-3-(phenylsulphonylamino)phenyl acetate.

M.p. 133–135° C.

PREPARATION 14 trans-Ethyl 1-(4-N-benzylaminocyclohexyl)benzoate

A mixture of cis and trans isomer is obtained by carrying out theprocedure as described in Preparation 10, but using4-(4-ethoxycarbonylphenyl)cyclohexanone instead of4-phenylcyclohexanone, which mixture is separated by flashchromatography, eluting with a 7/3 cyclohexane/ethyl acetate mixture.The compound of the title is obtained as a white solid (R.f. lowercompared to the cis isomer, which is semi-solid).

M.p. 74–76° C.

PREPARATION 153-(Methylsulphonyl)-5-[(2S)-oxyranylmethoxy]-1,3-benzoxazol-2(3H)-one(i) 5-Methylcarbonyl-1,3-benzoxazol-2(3H)-one

7.8 ml of triethylamine and 2.75 g (0.0093 mol) of triphosgene are addedto a mixture of 4.2 g (0.0277 mol) of 2-amino-4-methylcarbonylphenol in100 ml of THF, at 0° C. The mixture is stirred at room temperature for 1hour, poured into 100 ml of a 0.5N HCl solution and extracted with ethylacetate, the organic phase is dried and the solvent is evaporated off.The compound of the title is obtained.

M.p. 231–234° C.

(ii) 3-Methylsulphonyl-5-methylcarbonyl-1,3-benzoxazol-2(3H)-one

1.7 g (0.0096 mol) of the product of the previous step is dissolved in60 ml of anhydrous methylene chloride and 1.35 ml of triethylamine areadded to this, followed, at 0° C., by 0.75 ml (0.0096 mol) of mesylchloride under a nitrogen stream. The mixture is stirred at roomtemperature overnight. It is poured into water, the organic phase isdried and the solvent is evaporated off. The product is purified bychromatography, eluting with a 6/4 cyclohexane/ethyl acetate mixture.The compound of the title is obtained.

M.p. 140–143° C.

(iii) 3-Methylsulphonyl-1,3-benzoxazol-2(3H)-on-5-yl acetate

A mixture of 3.3 g (0.013 mol) of the product of the previous step and16.1 g (0.065 mol) of 3-chloroperbenzoic acid (MCPBA) in 200 ml ofmethylene chloride is refluxed for 48 hours. The mixture is cooled, andthen washed with a 20% Na₂S₂O₅ solution, followed by a saturated sodiumbicarbonate solution, a sodium iodide solution and water. The organicphase is dried and the solvent is evaporated off. The product ispurified by chromatography, eluting with a 75/25 cyclohexane/ethylacetate mixture. The compound of the title is obtained as a white solid.

M.p. 159–162° C.

(iv) 5-Hydroxy-3-(methylsulphonyl)-1,3-benzoxazol-2(3H)-one

735 mg (2.71 mmol) of the product of the previous step are dissolved in50 ml of ethanol and 2.06 g (10.84 mmol) of p-toluenesulphonic acid areadded to this. The mixture is stirred for 3 hours and then diluted with100 ml of methylene chloride. The mixture is washed with a sodiumbicarbonate solution, the organic phase is dried and the solvent isevaporated off. The compound of the title is obtained.

M.p. 129–130° C.

(v)3-(Methylsulphonyl)-5-[(2S)-oxyranylmethoxy]-1,3-benzoxazol-2(3H)-one

The compound of the title is obtained by carrying out the procedure asdescribed in Preparation 4 (iv), but using the product of the previousstep instead of4-benzyloxy-3-(N-tert-butoxycarbonyl-N-phenylsulphonylamino)phenol.

M.p. 100–102° C.

PREPARATION 165-(Methylsulphonyl)-7-[(2S)-oxyranylmethoxy]-2,3,4,5-tetrahydro-1,5-benzoxazepine(i) 7-Hydroxy-5-(methylsulphonyl)-2,3,4,5-tetrahydro-1,5-benzoxazepine

0.568 g (2.32 mmol) of 4-hydroxy-3-methylsulphonylaminophenyl acetate(obtained by hydrogenation of the corresponding benzyloxy derivative),0.672 g of potassium carbonate in 20 ml of DMF are mixed under anitrogen stream, and 0.259 ml of 1,3-dibromopropane is then added tothis. The mixture is stirred at room temperature overnight. Water isadded and the mixture is extracted with ethyl acetate. The organic phaseis dried and the solvent is evaporated off. A purple oil is obtainedwhich is taken up in 8 ml of methanol and 1.88 ml of 1M NaOH. Water isthen added, followed by picric acid until a neutral pH is obtained. Themethanol is evaporated off and the remaining mixture is extracted withethyl acetate. The organic phase is dried and the solvent is evaporatedoff. The product is purified by chromatography, eluting with a 7/3cyclohexane/ethyl acetate mixture. The compound of the title isobtained.

(ii) 5-(Methylsulphonyl)-7-[(2S)-oxyranylmethoxy]-2,3,4,5-tetrahydro1,5-benzoxazepine

The compound of the title is obtained as a white solid by carrying outthe procedure as described in Preparation 4 (iv), but using the productof the previous step instead of the product of step 4 (iii).

PREPARATION 174-(2-Trimethylsilylethoxymethoxy)-3-chloro-1-((2S)2,3-epoxypropoxy)phenol(i) 3-Chloro-4-(2-trimethylsilylethoxymethoxy)benzaldehyde

5 g (31.93 mmol) of 5-chloro-4-hydroxybenzaldehyde are dissolved in 300ml of methylene chloride and 6.7 ml (38.3 mmol) ofN,N-diisopropyl-N-ethylamine and 5.9 ml (33.52 mmol) of2-trimethylsilylethoxymethyl chloride (SEMCl) are added to this at 0° C.The mixture is allowed to return to room temperature and stirredovernight. Water is then added and the mixture is extracted withmethylene chloride. The organic phase is dried and the solvent isevaporated off. The product of the title is obtained, which is purifiedby chromatography on a silica gel column, eluting with a 95/5 and then9/1 heptane/ethyl acetate mixture.

(ii) 3-Chloro-4-(2-trimethylsilylethoxymethoxy)phenol

10.6 g of meta chloroperbenzoic acid at 70% are added to a mixture of7.5 g (26.14 mmol) of the product of the previous step in 260 ml ofmethylene chloride at 0° C. The mixture is allowed to return to roomtemperature and stirred overnight. A sodium bicarbonate solution is thenadded and the mixture is extracted with methylene chloride. The organicphase is dried and the solvent is evaporated off. The product of thetitle is obtained, which is purified by chromatography on a silica gelcolumn, eluting with a 9/1 cyclohexane/ethyl acetate mixture.

(iii)4-(2-Trimethylsilylethoxymethoxy)-3-chloro-1-((2S)2,3-epoxypropoxy)benzene

The compound of the title is obtained as a white solid by carrying outthe procedure as described in Preparation 4 (iv), but using the productof the previous step instead of the product of step 4 (iii).

PREPARATION 18 trans-N-[4-(4-Aminocyclohexyl)benzoyl]pyrrolidine

The compound of the title is obtained by carrying out the procedure asdescribed in Preparation 8 (iii) and (iv), but using pyrrolidine insteadof diethylamine.

PREPARATION 19 cis- andtrans-4-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]cyclohexanamine

The cis and trans mixture of the product of the title is obtained in aratio of approximately 3/7, by carrying out the procedure as describedin Preparation 3, but using4-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]cyclohexanone, andwithout adding to the mixture the ethanol saturated with hydrochloricacid. These isomers are separated by HPLC under the followingconditions:

-   Column: CHROMOLITH RP 18-   Eluent: KH₂PO₄ (0.05M), pH 3.5/acetonitrile=80/20-   Flow rate: 1 ml/min.-   λ: 254 nm-   TRR1: 1.00 (trans isomer)-   TRR2: 1.08 (cis isomer)

PREPARATION 20trans-1-(4-N-Benzylaminocyclohexyl)-4-ethylcarbonylbenzene (i)trans-1-(4-(N-Benzylamino-N-tert-butoxycarbonyl)cyclohexyl)benzonitrile

380 mg (1.3 mmol) of the product of Preparation 11 are dissolved in 4.5ml of THF and 343 mg (1.5 mmol) of di-tert-butyl dicarbonate and 0.220ml of triethylamine are added to this. The mixture is stirred at roomtemperature overnight, 40 ml of water are added, the aqueous phase isextracted with ethyl acetate, the organic phase is dried and the solventis evaporated off. The product of the title is thus obtained.

(ii)trans-1-(4-N-Benzylamino-N-tert-butoxycarbonyl)cyclohexyl-4-ethylcarbonylbenzene

1.06 g (2.72 mmol) of the product of the previous step are dissolved in40 ml of anhydrous toluene and 5.4 ml (5.43 mmol) of ethylmagnesiumbromide (EtMgBr) at the temperature of 0–5° C. are added to this under anitrogen stream. The mixture is stirred at room temperature overnight,50 ml of water are added, the aqueous phase is extracted with ethylacetate, the organic phase is dried and the solvent is evaporated off.The product of the title is thus obtained.

(iii) trans-1-(4-N-Benzylaminocyclohexyl)-4-ethylcarbonylbenzene

A mixture of 1.17 g (2.77 mol) of the product of the previous step and30.7 ml of a solution of trifluoroacetic acid in methylene chloride at15% is stirred at room temperature overnight. Ethyl acetate is thenadded and the mixture is washed with a sodium bicarbonate solution. Theorganic phase is dried and the solvent is evaporated off. The product ofthe title is thus obtained.

PREPARATION 21 trans-tert-Butyl 1-(4-N-benzylaminocyclohexyl)benzoate

The product of the title is prepared by trans-esterification of theproduct of Preparation 14, according to the method described in J.O.C.,1997, 62:8240.

EXAMPLE 1 trans-Ethyl4-[4-((2S)-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)-2-hydroxypropylamino)cyclohexyl]benzoate

Formula (I): A=(a); R₁=Bn; R=—NHSO₂-Me; n,m=0; R₃=4-COOEt

A mixture of 818 mg of4-benzyloxy-3-(N-tert-butoxycarbonyl-N-methylsulphonylamino)-1-((2S)2,3-epoxypropoxy)benzene(1.82 mmol) and 450 mg of the “trans” product obtained according toPreparation 3 in the form of a base (1.82 mmol) in 15 ml of absoluteethanol is refluxed for 16 hours. The mixture is cooled, 3 ml of asolution of ethanol saturated with hydrochloric acid are added to thisand the mixture is heated at 50° C. for 6 hours. The solvent isevaporated off and the residue is taken up with a mixture of 50 ml of asaturated sodium bicarbonate solution and 50 ml of ethyl acetate. Theorganic phase is washed with a saturated aqueous NaCl solution. Theorganic phase is dried and, after filtration, the solvent is evaporatedoff under reduced pressure. The crude product is purified bychromatography on a silica gel column, eluting with a 95/5/0.5 methylenechloride/methanol/NH₄OH mixture. The compound of the title is obtainedin the form of a white solid.

M.p. 132–134° C.

EXAMPLE 2 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoatehydrochlorate

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-COOEt

A solution of 500 mg of the product of Example 1 (838 mmol) in 25 ml ofa mixture of ethanol and THF is stirred at room temperature in ahydrogen atmosphere for 7 hours, in the presence of 400 mg of Pd/C at10%. The catalyst is filtered, the solvent is evaporated off underreduced pressure and the crude product is purified by chromatography ona silica gel column, eluting with a 95/5/0.5 methylenechloride/methanol/NH₄OH mixture. The compound of the title is obtainedin the form of a base. The hydrochlorate of this base is obtained bytreating it with a solution of hydrochloric acid in ethanol.

M.p. 183–185° C.

The product thus obtained is subsequently purified by crystallization inisopropanol.

M.p. 188–190° C.

EXAMPLE 3 cis-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-COOEt

3a. cis-Ethyl4-[4-((2S)-3-(4-benzyloxy-3-(N-methylsulphonylamino)phenoxy)-2-hydroxypropylamino)cyclohexyl]benzoate

The compound of the title is obtained as a vitreous white solid, bycarrying out the procedure as described in Example 1, but using the cisproduct of Preparation 3.

3b. cis-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of the previous stepinstead of the product of Example 1.

M.p. 135–138° C. (hydrochlorate)

EXAMPLE 4 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(phenylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

Formula (I): A=(a); R₁=H; R=—NHSO₂-Ph; n,m=0; R₃=4-COOEt

4a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-benzyloxy-3-(phenylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the epoxide of Preparation 4.

M.p. 113–115° C.

4b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(phenylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 4a instead ofthe product of Example 1.

M.p. 172–174° C. (hydrochlorate).

EXAMPLE 5 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(n-butylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

Formula (I): A=(a); R₁=H; R=—NHSO₂-nBu; n,m=0; R₃=4-COOEt

5a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-benzyloxy-3-(n-butylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the epoxide of Preparation 5.

M.p. 108–110° C.

5b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(n-butylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 5a instead ofthe product of Example 1.

M.p. 149–151° C. (hydrochlorate).

EXAMPLE 6 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(benzylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

Formula (I): A=(a); R₁=H; R=—NHSO₂-Bn; n,m=0; R₃=4-COOEt

6a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-benzyloxy-3-(benzylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained in the form of a vitreous whitesolid, by carrying out the procedure as described in Example 1, butusing the epoxide of Preparation 6.

6b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(benzylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

430 mg of the product of the previous step are dissolved in 7.5 ml oftrifluoroacetic acid and the mixture is heated at 60° C. for 3 hours.The solvent is evaporated off under reduced pressure and the residue istaken up in a mixture of aqueous sodium bicarbonate and ethyl acetate.300 mg of potassium carbonate are added and the two phases areseparated. The organic phase is washed with a sodium chloride solution,it is dried over sodium sulphate and the solvent is evaporated off underreduced pressure. The residue is purified by flash chromatography on asilica gel column, eluting with a 95/5/05 CH₂Cl₂/MeOH/NH₃ mixture. Thecompound of the title is thus obtained. Its hydrochlorate is preparedusing a solution of hydrochloric acid in ethyl acetate.

M.p. 170–172° C. (hydrochlorate).

EXAMPLE 7 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonyl)phenoxy)propylamino)cyclohexyl]benzoate

Formula (I): A=(a); R₁=H; R=—SO₂-Me; n,m=0; R₃=4-COOEt

7a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-benzyloxy-3-(methylsulphonyl)phenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using4-benzyloxy-3-methylsulphonyl-1-((2S)2,3-epoxypropoxy)benzene (describedin WO 99/65895), and without adding to the mixture the solution ofhydrochloric acid in ethanol.

M.p. 142–144° C.

7b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonyl)phenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 6b, but using the product of Example 7a instead ofthe product of Example 6a.

M.p. 173–175° C.

EXAMPLE 8trans-N-[5-[[(2S)-3-((4-(4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-phenyl)cyclohexyl)amino)-2-hydroxypropyl]oxy]-2-hydroxyphenyl]methanesulphonamide

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-Ox

8a.trans-N-[5-[[(2S)-3-((4-(4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-phenyl)cyclohexyl)amino)-2-hydroxypropyl]oxy]-2-benzyloxyphenyl]-N-benzyl-N-methanesulphonamide

The compound of the title, free of cis isomer, is obtained as a vitreoussolid by carrying out the procedure as described in Example 1, butwithout adding to the mixture the ethanol solution saturated with HCl,and using the epoxide of Preparation 7 and the product of Preparation19.

8b.trans-N-[5-[[(2S)-3-((4-(4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl)cyclohexyl)amino)-2-hydroxypropyl]oxy]-2-hydroxyphenyl]methanesulphonamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 8a instead ofthe product of Example 1.

M.p. 75–78° C.

EXAMPLE 9trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-N,N-diethylbenzamide

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-CONEt₂

9a.trans-4-[4-((2S)-2-Hydroxy-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-N,N-diethylbenzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the product of Preparation 8 insteadof the product of Preparation 3.

M.p. 48–50° C.

9b.trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-N,N-diethylbenzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 9a instead ofthe product of Example 1.

M.p. 69–72° C.

EXAMPLE 10trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-N-n-butylbenzamide

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-CONHBu

10a.trans-4-[4-((2S)-2-Hydroxy-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-N-n-butylbenzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the product of Preparation 9 insteadof the product of Preparation 3.

M.p. 138–140° C.

10b.trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-N-n-butylbenzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 10a instead ofthe product of Example 1.

M.p. 144–146° C.

EXAMPLE 11trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzene

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=H

11a.trans-4-[4-((2S)-2-Hydroxy-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)propyl-(N-benzyl)amino)cyclohexyl]benzene

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the product of Preparation 10 insteadof the product of Preparation 3, and eluting with 8/2 cyclohexane/ethylacetate.

11b.trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzene

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 11a instead ofthe product of Example 1.

M.p. 172–175° C.

EXAMPLE 12trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoicacid

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-COOH

A solution of 0.1167 g of the product of Example 2 (base) (0.33 mmol) ina mixture of 1.6 mL of methanol and of 1.6 mL of a 1N aqueous sodiumhydroxide solution is stirred for 4 hours. The acidified reaction mediumis then acidified by adding 1.6 mL of a 1N aqueous hydrochloric acidsolution, and then the mixture is diluted with methanol. The product ofthe title is obtained (0.08 g, yield=5%) in the form oftrifluoroacetate, after purification on preparative HPLC/MS andevaporation of the solvents.

Apparatus: two Shimatzu LC8 pumps coupled to a PE Sciex API 100 massspectrometer. An SCL-10A controller. A Gilson 215 injector-fractioncollector.

Stationary phase: Xterra MS C18, 50×30 mm, 5 μm

Mobile phase: Eluent A: 95/5 H₂O/MeOH+0.05% CF₃COOH

-   -   Eluent B: 5/95 H₂O/MeOH+0.05% CF₃COOH    -   Flow rate: 30 mL/min        Elution gradient:

t (in min) % A % B 0 90 10 3 90 10 15 10 90 17 10 90

TR=8.17 min, [M+H⁺]=479.3.

The purified product was analysed by HPLC under the followingconditions.

Apparatus: two Shimatzu LC8 pumps coupled to an SPD10-A UV-detector anda PE Sciex API 100 mass spectrometer. An SCL-10A controller. A Gilson215 injector-fraction collector.

Stationary phase: Xterra MS C18, 50×4.6 mm, 5 μm.

Mobile phase: Eluent A: 95/5 H₂O/MeOH+0.05% CF₃COOH

Eluent B: 5/95 H₂O/MeOH+0.05% CF₃COOH

-   -   Flow rate: 3 mL/min        Elution gradient:

t (in min) % A % B 0 90 10 1 90 10 9 10 90 10 10 90TR=4.79 min, [M+H⁺]=479.3

EXAMPLE 13trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzonitrile

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-CN

13a.trans-4-[4-((2S)-2-Hydroxy-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)propyl-(N-benzyl)amino)cyclohexyl]benzonitrile

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the product of Preparation 11 insteadof the product of Preparation 3, and eluting with 9/1 methylenechloride/methanol.

13b.trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzonitrile

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 13a instead ofthe product of Example 1, and using PdOH₂/C instead of Pd/C.

¹H NMR (CDCl₃+D₂O; ppm): 1.13–1.66 (4H; m); 1.77–2.00 (2H; m); 2.00–2.19(2H; m); 2.35–3.09 (4H; m); 2.89 (3H; s); 3.70–3.93 (2H; m); 3.96–4.16(1H; m); 6.42 (1H; dd; 9 Hz; 2 Hz); 6.72 (1H; d; 8 Hz); 6.92 (1H; d; 2Hz); 7.07–7.22 (2H; m); 7.48–7.64 (2H; m).

IR (KBr; cm⁻¹): 3430; 2227; 1324; 1151

EXAMPLE 14trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylaminophenoxy)propylamino)cyclohexyl]benzamide

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-CONH₂

14a.trans-4-[4-((2S)-2-Hydroxy-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)propyl-(N-benzyl)amino)cyclohexyl]benzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the product of Preparation 12 insteadof the product of Preparation 3, and eluting with 2/1 cyclohexane/ethylacetate.

14b.trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzamide

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 14a instead ofthe product of Example 1.

M.p. 79–81° C.

EXAMPLE 15 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-methoxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

Formula (I): A=(a); R₁=Me; R=—NHSO₂-Me; n,m=0; R₃=4-COOEt

15a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-methoxy-3-(methylsulphonylamino)phenoxy)propyl-(N-benzyl)amino)cyclohexyl]benzoate

The compound of the title is obtained as a vitreous solid by carryingout the procedure as described in Example 1, but using the product ofPreparation 13 and the product of Preparation 14, and eluting with 1/1cyclohexane/ethyl acetate.

15b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-methoxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 15a instead theproduct of Example 1.

M.p. 144–146° C.

EXAMPLE 16 trans-Ethyl4-[4-(((2S)-2-hydroxy-3-[(3-(methylsulphonyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]oxy)propyl)amino)cyclohexyl]benzoate

Formula (I): A=(b); X=CO; R₂=—SO₂Me; n,m=0; R₃=4-COOEt

16a. trans-Ethyl4-[4-(benzyl-((2S)-2-hydroxy-3-[(3-(methylsulphonyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]oxy)propyl)amino)cyclohexyl]benzoate

The compound of the title is obtained as a vitreous solid by carryingout the procedure as described in Example 1, but using the epoxide ofPreparation 15 and the product of Preparation 14, but without adding tothe mixture the solution of ethanol saturated with HCl, and eluting with1/1 cyclohexane/ethyl acetate.

16b. trans-Ethyl4-[4-(((2S)-2-hydroxy-3-[(3-(methylsulphonyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-oxy)propyl)amino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 16a instead ofthe product of Example 1.

M.p. 146–148° C.

EXAMPLE 17 trans-Ethyl4-[4-((2S)-2-hydroxy-3-((5-methylsulphonyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-yl)oxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

Formula (I): A=(b); X=CH₂CH₂CH₂; R₂=—SO₂Me; n,m=0; R₃=4-COOEt

17a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-((5-methylsulphonyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-yl)oxy)propyl-(N-benzyl)amino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the epoxide of Preparation 16 and theproduct of Preparation 14, and without adding to the mixture thesolution of ethanol saturated with HCl, and eluting with 98/2 methylenechloride/ethanol.

17b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-((5-methylsulphonyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-yl)oxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of Example 17a instead ofthe product of Example 1.

M.p. 170–173° C. (hydrochlorate).

EXAMPLE 18 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-chlorophenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

Formula (I): A=(a); R₁=H; R=Cl; n,m=0; R₃=4-COOEt

18a. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-(2-trimethylsilylethoxymethoxy)-3-chlorophenoxy)propylamino)cyclohexyl]benzoate

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the epoxide of Preparation 17, andwithout adding to the mixture the solution of hydrochloric acid.

18b. trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-chlorophenoxy)propylamino)cyclohexyl]benzoateand its hydrochlorate

A mixture of 0.34 g (0.588 mmol) of the product of the previous step,0.46 g (1.76 mmol) of tetrabutylammonium fluoride and 0.2 ml ofhexamethylphosphoramide in 5 ml of THF is refluxed overnight. Thesolvent is evaporated off, the residue is taken up with ethyl acetateand washed with water, the organic phase is dried and the solvent isevaporated off under reduced pressure. The crude product is purified bychromatography on a silica gel column, eluting with a 95/5 and then a90/10 CH₂Cl₂/EtOH mixture. The compound of the title is obtained. Thehydrochlorate of the base is obtained by treating it with a solution ofhydrochloric acid in ethyl ether.

M.p. 223–225° C.

EXAMPLE 19trans-N-[4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-methylsulphonylaminophenoxy)propylamino)cyclohexyl]benzoyl]pyrrolidine

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-CO-pyrrolidino

19a.trans-N-[4-[4-((2S)-2-Hydroxy-3-(4-benzyloxy-3-methylsulphonylaminophenoxy)propylamino)cyclohexyl]benzoyl]pyrrolidine

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the product of Preparation 18 insteadof the product of Preparation 3.

19b.trans-N-[4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-methylsulphonylaminophenoxy)propylamino)cyclohexyl]benzoyl]pyrrolidine

The compound of the title is obtained by carrying out the procedure asdescribed in Example 2, but using the product of previous step insteadof the product of Example 1.

[α]_(D)=−1.6° (c=0.264, EtOH)

EXAMPLE 20 trans-Ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxyphenoxy)propylamino)cyclohexyl]benzoate

Formula (I): A=(a); R₁=H; R=H; n,m=0; R₃=4-COOEt

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using4-benzyloxy-1-((2S)2,3-epoxypropoxy)benzene and without adding to themixture the solution of hydrochloric acid, and then according to Example2.

M.p. 146° C.

EXAMPLE 21trans-4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]-1-ethylcarbonylbenzene

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-COEt

The compound of the title is obtained in the form of a light brownsolid, by carrying out the procedure described in Example 1, but usingthe product of Preparation 20 instead of the product of Preparation 3and eluting with 7/3 cyclohexane/ethyl acetate mixture, and thenaccording to Example 2, but using PdOH₂/C instead of Pd/C.

¹H NMR (DMSO-D6+D₂O 313K; ppm): 1.08 (3H; t; 7 Hz); 1.37–1.68 (4H; m);1.73–2.00 (2H; m); 2.05–2.29 (2H; m); 2.42–2.70 (2H; m); 2.82–3.21 (4H;m); 2.94 (3H; s); 3.80–3.99 (2H; m); 4.03–4.22 (1H; m); 6.53–6.74 (1H;m); 7.74–6.96 (2H; m); 7.30–7.54 (2H; m); 7.79–8.02 (2H; m).

EXAMPLE 22 trans-tert-Butyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate

Formula (I): A=(a); R₁=H; R=—NHSO₂-Me; n,m=0; R₃=4-COO-tBu

A mixture of 782.4 mg (1.78 mmol) of the epoxide of Preparation 7 and650 mg of the product of Preparation 21 (1.78 mmol) in 9 ml oftert-butyl alcohol is refluxed for 16 hours. The solvent is evaporatedoff under reduced pressure, and the product is purified bychromatography on a silica gel column, eluting with 1/1 methylenechloride/ethyl acetate. A solution of 880 mg of the product thusprepared in 30 ml of THF is hydrogenated at room temperature for 7 hoursin the presence of 264 mg Pd/C at 10%. The catalyst is filtered, thesolvent is evaporated off under reduced pressure and the crude productis purified by chromatography on a silica gel column, eluting with THF.The compound of the title is obtained, which is purified by treatmentwith n-pentane.

¹H NMR (DMSO-D6+D₂O 313K; ppm): 1.10–1.28 (2H; m); 1.38–1.65 (2H; m);1.53 (9H; s); 1.70–1.1.90 (2H; m); 1.90–2.09 (2H; m); 2.41–2.71 (3H; m);2.71–2.83 (1H; m); 2.94 (3H; s); 3.72–3.95 (3H; m); 6.61 (1H; dd; 9 Hz;3 Hz); 6.78 (1H; dd; 9 Hz); 6.82 (1H; dd; 3 Hz); 7.28–7.37 (2H; m);7.75–7.85 (2H; m).

EXAMPLE 23trans-4-[4-(((2S)-2-Hydroxy-3-[(3-(methylsulphonyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-oxy)propylamino)cyclohexyl]benzamide

Formula (I): A=(b); X=CO; R₂=—SO₂Me; n,m=0; R₃=4-CONH₂

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the epoxide of Preparation 15 and theproduct of Preparation 12, and without adding to the mixture thesolution of ethanol saturated with HCl, and then as described in Example2.

¹H NMR (DMSO-D6; 313K; ppm): 1.03–1.29 (2H; m); 1.387–1.63 (2H; m);1.72–1.90 (2H; m); 1.90–2.11 (2H; m); 2.35–2.48 (1H; m); 2.52–2.84 (3H;m); 3.39 (3H; s); 3.68–3.84 (1H; m); 3.84–4.02 (2H; m); 7.09 (1H; dd; 9Hz; 3 Hz); 7.25–7.33 (2H; m); 7.38 (1H; d; 3 Hz); 7.41 (1H; d; 9 Hz);7.73–7.82 (2H; m).

IR (KBr; cm⁻¹): 3381; 3203; 1770; 1657.

1. A compound, which is ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoateor a salt or solvate thereof.
 2. A process for preparing the compoundaccording to claim 1, wherein (a) a compound of formula (II):

wherein A is 4-hydroxy-3(methylsulphonylamino)-phenyl is reacted with anamine of formula (III):

wherein n is O, m is O and R₃ is ethoxycarbonyl attached to the paraposition of the phenyl ring, and optionally, the compound according toclaim 1 thus obtained is transformed into a salt or solvate thereof. 3.A pharmaceutical composition comprising the compound according to claim1 or a pharmaceutically acceptable salt or solvate thereof, togetherwith a pharmaceutical excipient.
 4. A method for delaying preterm birthin a patient in need thereof comprising administering to the patient aneffective amount of the compound according to claim 1 or a salt ofsolvate thereof.
 5. The compound according to claim 1, which istrans-ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate or a salt or solvate thereof.
 6. The salt accordingto claim 5, which is trans-ethyl4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoate hydrochlorate.